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One in five deaths in the US is related to tobacco use, accounting for 30% of all cancer deaths and 87% of lung cancer deaths. Smoking increases the risk of many types of cancer including nasal cavity, lip, oral cavity, lung, pancreas, and acute myeloid leukemia. Lung cancer accounts for about 15% of cancer diagnoses, and is the most deadly disease in both men and women. Cigarette smoking cause 80,000 lung cancer deaths for men and 45,000 for women annually. The five-year survival rate is only 16%, and mostly limited to patients with early diagnosis. Understanding of the initiation process of lung and other tobacco-related cancers is vital to eradicate these horrible diseases, which is the focus of this proposal.
Secondhand smoke, or environmental tobacco smoke (ETS), contains many varieties of carcinogens above safe exposure levels, very similar to tobacco smoke. Benzo[a]pyrene is a highly toxic carcinogen found in tobacco smoke. Its metabolic product likely contributes to cancer initiation after smoke exposure by distortion of the genetic material DNA and stalling of replication fork during normal cell divisions. Homologous recombination is the high-fidelity DNA repair pathway to restart stalled replication fork when the fork encounters damages caused by genotoxins found in tobacco smoke. Thus, functional homologous recombination machinery is key to active DNA repair and cancer prevention. The critical role of homologous recombination is reflected by the lethal phenotypes of recombination protein mutants, embryonic lethality and severe chromosome aberration. Impaired HR pathway leads to genomic instability, and as a consequence, neoplastic transformation and cancer initiation. Consequently, patients with the mutations in genes involved in HR have severe cancer predisposition diseases. One of these genes is human cancer tumor suppressor protein BRCA2, the target gene of our research proposal.
The systemic and critical role of BRCA2 is reflected by the clinical findings that BRCA2 mutations are associated with highly increased risk in pancreatic cancer, oral cavity and throat cancers, and lung cancer. The strongest known risk factor for cancers in these four sites is cigarette smoking, or exposure to ETS. Several studies also demonstrated that both allelic imbalance at BRCA2 gene and low BRCA2 protein expression level were associated with lung cancer, especially in non-small cell lung carcinomas. Thus, knowledge about the biological role of the BRCA2 protein in tumor suppression will provide insights into new approaches to prevent, detect, and treat lung and other forms of tobacco-related cancers.
I propose to study the molecular functions and structural information of human BRCA2 protein and compare the differences between wild type BRCA2 protein and cancer-causing defective BRCA2 mutant proteins, using a multidisciplinary approach. My research directly targets the biological basis of hereditary cancer and will contribute greatly to a better understanding of the etiology. Better understanding of the lung and tobacco-related cancer initiation process will also significantly advance future development of potential prognostic biomarkers of clinical outcome, since clinical analysis has shown that genetic variations of BRCA2 gene is predictive of lung cancer outcome. Furthermore, 3D structures of wild type and mutant BRCA2 proteins and their complexes with Rad51 will be obtained from this study. The structural information is not only a breakthrough in the field but also provides new direction in future potential structure-based drug design and screen. |
